Acute -on- Chronic liver failure – Terminology, Mechanisms and Management.

Vinay Kumar BR, Shiv Kumar Sarin

Department of hepatology, Institute of Liver and Biliary Sciences, New Delhi.

# Authors contributed equally

Correspondence:

Dr. Shiv Kumar Sarin, MD, DM, DSc (Hony.)

Senior Professor

Department of Hepatology,

Institute of Liver and Biliary Sciences, New Delhi-110070, India

Tel: 011-46300000, Fax 011-26123504

E-mail: shivsarin@gmail.com

Disclosure: All authors have no conflict of interest.

Key Words: Bile acid profile, extracorporeal liver support system, ACLF, Organ failure,
Abstract:

Acute on chronic liver failure (ACLF) is an acute deterioration of liver function

manifesting as jaundice and coagulopathy with the development of ascites, with a high

probability of extrahepatic organ involvement and high 28-day mortality. The

pathogenesis involves extensive hepatic necrosis, which is associated with severe

systemic inflammation and subsequently causes the cytokine storm, leading to portal

hypertension, organ dysfunction, and organ failure. These patients have increased gut

permeability, releasing lipopolysaccharide (LPS) and damage-associated molecular

patterns (DAMPS) in the blood, leading to hyper-immune activation and the secretion of

cytokines, followed by immune paralysis, causing the development of infections and

organ failure in a proportion of patients. Early detection and the institution of treatment,

especially in the "Golden Window" period of 7 days, give an opportunity for reversal of

the syndrome. Scores like the APASL ACLF research consortium (AARC) score, a model

for end stage liver disease (MELD), and the CLIF Consortium acute-on-chronic liver

failure (CLIF C-ACLF) score can help in the prediction of mortality. Treatment strategy

includes treatment of acute insult. Patients should be considered for early transplant with

MELD score >28, AARC score >10, high-grade HE, and in the absence of > 2 organ

failure or overt sepsis as there is a high chance of failure of conservative management and

high mortality to improve survival of up to 80% at five years after liver transplantation.

Patients, with no option of transplant, can be treated with emerging therapies like faecal

microbial transplant, plasma exchange, etc., which need further evaluation.

Introduction

Acute-on-chronic liver failure (ACLF) is an acute deterioration in the function of the liver,

with significant systemic inflammation and high short-term mortality. (1) People with liver

failure have a very high mortality and morbidity rate. The list of causes of liver failure is

constantly growing, and treating these patients is certainly very challenging. Liver failure

can manifest as acute liver failure or as ACLF. When an acute insult causes liver failure

in a patient with underlying chronic liver disease, it is referred to as ACLF. While various

societies define the ACLF condition differently, the symptoms usually involve acute

deterioration of liver function manifesting as liver failure and other non-hepatic organ

failures with high short-term mortality. (1)

Current definitions and concept

Asian Pacific Association for Study of Liver (APASL) has defined this condition as a

syndrome with an acute hepatic insult manifesting as jaundice (serum bilirubin ≥ 5 mg/dl

(≥ 85 micromole/l) and coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%)

complicated within 4 weeks by clinical ascites and/or hepatic encephalopathy (HE) in a

patient with previously diagnosed or undiagnosed chronic liver disease, i.e., with or

without cirrhosis, with high 28-day mortality. While EASL defines it as acute
(1,2)
decompensation in a cirrhotic patient with or without prior decompensation. The

difference between APASL, EASL, and the North American Consortium for the Study of

End-Stage Liver Disease (NACSELD-ACLF) criteria is shown in table 1. According to

the APASL definition, ACLF does develop in patients with grade 3 or 4 fibrosis and not
necessarily in cirrhosis. This has been elucidated in Figure 1, which shows the spectrum

of the disease and various definitions from different societies. (1,2)

Baveno VII guidelines suggested the concept of compensated advanced chronic liver

disease (cACLD) in 2021 to describe the continuum of severe fibrosis and cirrhosis in

patients with chronic liver disease based on liver stiffness measurement (LSM). This

helps in stratifying the risk of clinically significant portal hypertension (CSPH) and
(3)
decompensation at the point of care. Studies have shown that if ACLF patients survive

the first 4 weeks of illness, they have a high chance of resolution of ascites, jaundice, and

hepatic encephalopathy. (1,2)

Epidemiology and pathogenesis

ACLF is a severe medical ailment that affects a large population across the globe. Its

prevalence ranges from 20–35% among the population at risk, for example, those

suffering from viral hepatitis (HBV or HCV infection), excessive alcohol intake, or
(1-4)
suffering from NASH, etc. With the rising epidemics of obesity and NASH, the

proportion of ACLF is bound to rise with increased mortality. As demonstrated in a

follow-up study of 80,383 cirrhosis patients for 3.5 years, 574 (APASL definition), 4276
(1-6)
(EASL definition), and 783 (both definitions) patients developed ACLF. Mortality

was also high among grade III ACLF patients, with a mortality rate of up to 74% versus

1.9 percent among those without ACLF presentation. (7-10)

Acute precipitating events and chronic insults

Acute precipitating events:

The precipitating events can be classified as hepatic or non-hepatic, among the most

common causes are a reactivation of the chronic hepatitis B viral (HBV) infection, acute

hepatitis A and E (HAV/HEV) infection, alcohol-associated hepatitis (AH), and an acute

bacterial infection. Among the Asian population, precipitating events can be identified in

95% of cases. (1) While in the western population, alcoholism and bacterial infection were
(2)
important triggering events, which can be identified among 60% of cases at

presentation. (11, 12) HAV is responsible for 10–30% of acute hepatitis and about 5–15% of
(18)
liver failure cases in India. Hepatitis E virus (HEV) infection is endemic in Asia and
(20)
Africa, with a median incidence of 21% (range 4–72%). In India, HEV accounts for

10–40% of acute hepatitis and 15–45% of liver failure. In the west, the frequency is low,
(21-23)
with a French study quoting an incidence of 3.2%. since any chemical or drug is

mostly metabolised by the liver using an effective cytochrome system. The possible drug-

induced liver injury usually presents as acute liver failure. Studies involving ACLF
(26)
patients are few. However, most studies like Devarbhavi et al. showed that they have

high mortality, up to 17%. In a multinational Asian study of 660 patients, DILI

contributed as an acute insult in 9.1% of patients, and in 53.3% of these patients, the acute

insult was attributed to anti-tubercular drugs followed by complementary alternative

medications. (27)

Chronic underlying liver conditions:

Viral causes: In some regions, chronic HBV and HCV are important causes of underlying
(13-15)
chronic liver disease or cirrhosis. It is estimated that 325 million people worldwide

are living with chronic HBV or HCV infection. (16) HBV infection can present as an acute

infection in a patient with CLD due to another aetiology or HBV reactivation of chronic

HBV infection, which can be spontaneous or due to chemotherapy or immunosuppression

therapy, etc. ACLF-HBV-related is associated with mortality ranging from 30% to 70%.
(17)
Hepatitis B surface antigen (HBsAg) positivity in the general population ranges from

1.1% to 12.2%, with an average prevalence of 3-4%. Chronic HBV infection is seen in

approximately 40 million people, accounting for 20% of cases of cirrhosis and 40% of
(16-18)
HCC cases. In published data from coastal India, among the 123 ACLF patients,

HBV-related disease presentation was seen in 11.3%. (19)

Anti-HCV antibody prevalence in the general population is estimated to be between 0.09

and 15%. As per the available data, about 1.75 million people were estimated to be newly

infected with HCV in 2015, increasing the total number of people living with Hepatitis C

to 71 million.

Alcohol: It is one of the important precipitant causes. A recent history of binge drinking

plays a key role in precipitating ACLF with alcoholic hepatitis. Patients with significant

alcohol intake, present with alcoholic hepatitis with jaundice and no other obvious cause

for hepatitis. (1,24)

Non-alcoholic fatty liver disease: With the epidemic of obesity increasing all over the

world, NAFLD is fast becoming one of the leading causes of underlying chronic liver

disease. (1,28)

The pathophysiology involves the accumulation of reactive oxygen species, which plays

an important role in leading to apoptosis. Hepatic injury leads to the release of various

cytokines with inhibition of survival genes (Met) and induction of proapoptotic signalling

molecules (TNF and perforin and apoptosis stimulation fragment ligand known as FAS

ligand (FasL) which accelerates apoptosis which is demonstrated in fig 2. (25)

Liver failure is a driver of inflammation, organ failure, and sepsis.

APASL's definition encompasses a more similar group of patients, where liver failure

drives extrahepatic organ failure and mortality. It can help in detecting these patients in

the early part of the illness. (3) It also identifies the separate group of patients who develop

decompensation in patients with known CLD or cirrhosis or prior decompensation, which

(1,5)
develops in less than 3 months and is known as acute decompensation (AD). This is

in comparison to the western ACLF definition, which includes organ failure in the

definition and sepsis as one of the prominent precipitating causes in the criteria. In a

nutshell, the western definition includes acute decompensation of cirrhosis with the

presence of organ failures (hepatic and extrahepatic) and hence has very high short-term

mortality. (5,6)

Infection, especially a bacterial infection, is present in about 1/3 of the patients at

presentation and, when associated with organ failure (OF), has an increased risk of

mortality. A decompensated cirrhosis patient with infection has an 8% mortality rate,

while an infected ACLF patient with 1 OF has a 27% mortality rate, and the rate increases
(29)
to 77% with 4 OF. Similarly, patients with infection and sepsis had a high chance of

cerebral failure (31% vs. 10%), circulatory failure (34% vs. 18%), and respiratory failure

(20% vs. 10%) when compared to patients without the infection. Infected patients had
(30,31)
higher mortality, i.e., with infection vs. without infection, of 51% vs. 35%. Since

infection itself can result in liver failure, the inclusion of both extrahepatic organ failure

and sepsis in the definition of ACLF would, therefore, delay diagnosis in all cases and

also permit the inclusion of a heterogeneous group of patients.

Golden window period and critical functioning hepatic reserve

The initial 1-week period from the symptom onset and presentation is very important and

usually, the necrosis of the liver produces a systemic inflammatory response (SIRS),
which has several important consequences. The prime drivers of the patient outcome at

different time points are a combination of the critical functional hepatic reserve and the

nature and severity of the acute insult. Once SIRS develops, it augments further systemic

inflammation, leading to extrahepatic organ failure. So, this period up to the development

of immune paralysis and subsequent development of sepsis is considered the "golden

window of opportunity." This "golden window" period can be modulated using immune -

modulation therapy, etc., for the prevention of SIRS progression and the development of

organ failure, thus changing the course of the disease (Fig. 3). (1,32)

Clinical features and natural history

As mentioned in the definition, liver failure, i.e., the development of jaundice and

coagulopathy, is an important event. Later, these patients will develop ascites and

encephalopathy in the form of altered consciousness, which can range from trivial
(1,3)
unawareness to a significant coma. Other clinical features that can be present at the

time of presentation are acute variceal bleeding or presentation with an infection like

pneumonia, spontaneous bacterial peritonitis (SBP), urinary tract infection (UTI), etc.

Reactivation of HBV infection and acute HAV/HEV infections are usually associated

with symptoms of fatigue, fever, and other prodromal symptoms. A history of intake of

complementary and alternative medicines (CAMs) or treatment of tuberculosis (TB)

infection with anti-tubercular therapy could also be present. (1,2,33) In the AARC database,

among 1028 patients, 15% had obesity, 14% had T2DM, 7% had HTN, and 15% had
(1,34)
dyslipidaemia. ACLF patients generally have higher MELD scores and high AARC

scores with high mortality (Table 3). In the Canonic study, a prior history of
(1)
decompensation was present in up to 23% of the patients. Usually, the presence of

decompensation favours the diagnosis of AD.

Role of the liver biopsy

Patients with ACLF are often sick with severe coagulopathy, so invasive procedures

might be risky. However, liver biopsy with a trans-jugular route is considered safe, and

percutaneous biopsy could be unsafe due to coagulopathy and bleeding risk. In some

patients where trans-jugular cannot be performed, one can also try for laparoscopic liver

biopsy. (35)

ACLF generally has pathologic findings of fibrous bands (spurs or bridges) and ductular

proliferation. While the features of bile duct proliferation and cholestasis are common in
(35)
acute injuries, Diagnostic stains for fibrosis or necrosis can be performed (using

Shikata’s orcein stain). Rastogi et al. have proposed two patterns that predict patient

outcomes when comparing those who survived to those who died (box 1; Fig. 4). Pattern I

is associated with high mortality, and pattern II is associated with better survival,

irrespective of the etiology. (35)

Sub-massive hepatic necrosis is characterised by extensive and confluent necrosis,

cholestasis, and ductular bilirubinostasis, and it is predictive of poor outcomes in patients

with HBV-related ACLF. The extent of necrosis, liver damage, and fibrosis are important;

the finding of bilirubinostasis and eosinophilic degeneration of hepatocytes usually has an

(35,36)
unfavourable outcome, while ballooning can denote the potential for regeneration.

Other methods, like transient elastography, may be helpful to see the extent of fibrosis,

etc. but needs more data on reliability (Fig. 4). (36)

Organ failure and outcome assessment in ACLF patients

Renal failure
According to EASL, renal involvement is an important organ failure, and it is
(2)
incorporated in the case definition at the time of presentation. While in the APASL

definition, the cohort showed that AKI was present in 30% and that it further developed

in another 23%–34% during the course of the disease. Splanchnic vasodilation with

hormonal abnormalities forms the basis of the pathogenesis; SIRS and sepsis also play a
(36,37)
very definitive role. These patients usually show a partial or full response with

stoppage of diuretics and after 2 consecutive days of plasma volume expansion with
(1,38)
albumin with no intrinsic renal disease and a normal renal ultrasound. An acute

tubular necrosis (ATN) patient is unlikely to recover with medical management and may
(1,38)
require a simultaneous liver and kidney transplant (SLK). During the treatment, the

resolution of AKI has a good prognosis (38–40%), and the progression of AKI has a
(38-41)
mortality rate of approximately 75%. Biomarkers like NGAL, KIM-1, and IL-18

can be of some help in predicting renal failure and the development of ATN. (38-42)

Cerebral failure

It is usually defined using West Haven criteria; grades III–IV are considered to be

cerebral failure. Its pathophysiology is very complex, with neuroinflammation and

(43)
impairment of brain energy metabolism resulting in cerebral oedema. The arterial

ammonia can be measured, and it is a good surrogate marker for the severity of hepatic

encephalopathy (HE) in the advanced stages of ACLF, i.e., grades III–IV. The ammonia

level above 140 mg/dl at baseline or at any time point in the first week with grades III–IV

HE is considered a poor prognostic marker for 28- and 90-day survival (p<0.001), as

demonstrated in a study done in India. (1,43)

Coagulation failure

SIRS and sepsis have a significant role in inducing and progressing the coagulation defect.
(44)
The main mechanism of the defect is due to systemic inflammation and endothelial
dysfunction, which is well demonstrated in the study by Premkumar et al. In this study, it

showed that a hypo-coagulable thromboelastography (TEG) at baseline was a predictor of

bleeding [HR 2.1; CI 1.6-4.9; (p =0.050)] and mortality [HR 1.9; CI 1.3- 7.9;(p=0.043)].
(45)
This can also be because ACLF has increased heparinoids, which affect coagulability.
(46)
Dynamic coagulation parameters are measured by TEG or other point-of-care (POC)

tests and determine the likelihood of bleeding and mortality in ACLF. Studies have shown

that parameters like activated clotting time (ACT), clot rate (CR), platelet function (PF),

time to peak (TP), peak amplitude (PA), and fibrinogen levels are important predictors.

Using these, a score was developed called the "bleeding risk score," which was validated

in the study. ACT > 190 s, PF 1.25, and fibrinogen <1.2 g/l could predict coagulopathic

bleeding. The bleeding risk score ranges from 3 to 9. The coagulopathic bleeding

increases as the score increases from 3 to 9. (45) The POC tests can be helpful in situations

where correction is required, and they also reduce unnecessary transfusion and can be

helpful in guiding LT or major surgery. (1)

Circulatory failure and Respiratory failure

(2,62)
EASL defines circulatory failure as hypotension requiring vasopressors. The

dysfunction is considered when MAP < 70 mm of hg, while NASCELD defines failure as

MAP < 60mmhg or reduction of systolic blood pressure of 40 mm of hg from

(2,5,63)
baseline. Sepsis and SIRS play an important role. Respiratory failure is defined as

the need for mechanical ventilation, or PaO2/FiO2 < 200 or SpO2/FiO2 < 214. (5,51) Table

2 shows organ failure definitions according to various societies. Various definitions are

tabulated in table 2.

Assessment of outcome.
The outcome of ACLF is poor, especially when organ failures are present at presentation

or develop in the early weeks of ACLF, and mortality is as high as 40–50%. (47) Thus, the

early part of the week provides a "golden window of opportunity," as discussed earlier,

with effective therapy showing improved clinical outcomes. As for the other causes of

CLD, common scores like MELD-Na scores or CTP scores are used for prognosticating

and for allocating organs for liver transplantation as for the other causes of CLD. Since

ACLF is a progressive disease that warrants continuous monitoring, no single score can

assess and predict the outcome or suggest treatment options as seen in other diseases.

CTP/ MELD /Lille’s score

Chen et al showed that CTP >12 and MELD >28 were very independently predictive of

mortality in ACLF patients. Not only does static score help us to predict, but also during

the course, if there was no improvement in the MELD score after treatment on day 7, like

in patients of Autoimmune hepatitis (AIH), suggests urgent expedition for transplantation.

(48)
The Lille model was used in the same way after corticosteroid use for alcoholic

hepatitis and can help in predicting steroid non-responders and advising LT as a treatment

option. This becomes very important as Mathurin et al, showed that early LT improved

survival with cumulative survival (77%  8% versus 23  8%, p<0.001) with acceptable

low alcohol relapse. (24)

CLIF- C ACLF and CLIF- SOFA scores

If we look at the overall picture, the above scores lack a good predictive ability for

survival among ACLF patients. These scores do not include organ failures like

encephalopathy, vasopressor support, etc., which can predict poor outcomes. So other

scoring systems, which include dynamic parameters have been proposed by various

societies like chronic liver failure sequential organ failure (CLIF- SOFA), chronic liver

failure consortium (CLIF-C OF score), Asia Pacific Association for Study of Liver
 (1)
(APASL) ACLF Research Consortium (AARC) score, etc. About 11.3 % of patients

with acute decompensation developed ACLF within 28 days of enrolment in the

CANONIC study, and 50 % of these patients died within 3 months. (5) The CLIF-C acute

decompensation score was developed based on independent predictors of mortality (age,

white blood cell count, serum sodium, creatinine, and INR) in patients with acute
(49)
decompensation but without ACLF. A score of 45 or less was associated with a 3-

month mortality rate of 1.8%, representing a low-risk group that may be discharged early

with de-escalation of care. A score of 60 or more represents a high-risk group with a 3-

month mortality rate of 31 percent and a greater likelihood of progression to ACLF,

hence requiring escalation of care. (49)

Similarly, a CLIF-C ACLF score ≥ 70 at 48 hours predicts mortality more accurately,

with an AUROC of 0.643 (confidence interval [CI] 95% 0.505-0.781; p = 0.046), which

is significantly higher than MELD scores at 48 hours. In another study, it was shown that

if LT is contraindicated or cannot be available for patients with ≥4 organ failures or

CLIF-C ACLFs >64 at days 3–7 after the diagnosis of ACLF grade 3, intensive organ

support can be discontinued owing to futility (Table 3). (83)

The AARC score

This score uses five parameters like serum bilirubin, lactate, creatinine, INR, and HE.

Each parameter scored 1-3, with these parameters, the total score is later calculated and it

is classified into different grades like grade I (5-7), grade II (8-10), and grade III (11-15).

The analysis of the data showed 28-day mortality rates of 12.7%, 44.5%, and 85.9%,

respectively, among the 3 groups. Its dynamicity is excellent; it is accurate in the

prediction of survival on days 7 and 28; scores < 10 have better survival, and for each

unit raised above 10, the day 7 mortality increases by about 20%. AARC score >11 at

baseline or persisting after 1 week of treatment is associated with poor survival (p<
0.001). (34) Similarly, when compared to baseline AARC scores, any shift from grade I to

III on day 4 or day 7 has higher mortality. If the grade III ACLF state persists at day 7,
(1,50)
the prognosis is poor, and early liver transplantation should be considered. Various

scores are tabulated in table 3.

Treatment: An Algorithmic Approach

As ACLF patients often suffer from underlying chronic liver disease, they need holistic

care. Moreover, these patients have a rapid downward course with high short-term

mortality rates; treating such patients requires careful assessment, monitoring, and proper

ICU care. In view of the short window of opportunity, they need continuous and dynamic

monitoring with the backup of a liver transplant unit. Additionally, facilities for organ

support and bridging therapies should also be available. Management of ACLF needs a

proper multidisciplinary team approach with the hepatologist, intensivist, infection

control team, and transplant team for optimal management. Figure 5 gives a simple

algorithm for approaching the management.

The basics of management include:

• Treating the precipitating causes, which are usually correctable. Usually, grade I

and II ACLF patients will respond well.

• Identification of the complications and their management

• Identifying organ dysfunction, preventing organ failures, and, if needed, providing

prompt organ support. (34)

• For proper assessment, dynamic monitoring of the patients and the use of ACLF-

specific scores are necessary.

Nutrition

ACLF patients usually present early and have, clinically, a better nutritional status in

comparison to decompensated cirrhosis patients with worsening clinical status. However,

during the illness, especially in these patients with SIRS, the provision of high calorie and
(70)
protein intake, oral or parenteral, is essential. These patients require nutrition of
(51,52)
approximately 35–40 kcal/kg/day with a protein intake of 1.2-2 g/kg (IBW)/day. In

some cases, enteral feeding (through NG feeding with 1.5–2.0 kcal/ml feed) along with

enriched intake of the omega fatty acid may be beneficial, especially among those, who

cannot take the appropriate amount orally, especially those who are critically ill or

comatose and admitted in the ICU. The use of branched-chain amino acid supplements

may be beneficial. (53)

Infections

Up to 50% of patients with ACLF in general and more than 80% of critically ill patients
(54-56)
with ACLF grade 3 develop infections during their hospital stay. Fungal infections

are also very common and can be seen in patients with risk factors like diabetes, AKI,

ICU admission, prolonged hospitalisation, prior and prolonged antibiotic usage, etc.

These fungus infections can be proven, probable, or possible. (57)

Septic shock is identified by the requirement of vasopressors to maintain a mean arterial

pressure (MAP) of ≥65 mm Hg and a serum lactate level >2 mmol/L. Organ dysfunction

is defined as an increase in the Sequential Organ Failure Assessment (SOFA) score of ≥2

points. (55)

The choice of antibiotics depends on the type, severity, and origin of the infection

(community-acquired or nosocomial) and on local epidemiological data on antibiotic

resistance. Empirical antibiotics are started early, as every hour without adequate
treatment, mortality rates increase by about 3.3%. In a recent randomised controlled trial

of 143 ACLF patients, norfloxacin was shown to prevent bacterial infections and

improve transplant-free survival at day 90 as compared to placebo [58.3% (95% CI,

(58)
46.11–69.84) versus 43.7% (95% CI, 31.91–55.95), respectively (P = 0.058)]. Once

there is improvement in the condition or cultures are available after 48 hours, suitable

antibiotics can be given according to the cultures. Antifungal drugs are also

recommended in selected patients. As discussed earlier, echinocandins can be used in

resistant infections and in some suspected invasive aspergillosis infections, which are

increasing in incidence and may require IV amphotericin B for the treatment. (55,56)

Specific treatment of acute insult

Viral causes

Early detection and treatment of viral infections can reduce the progression of hepatic

injury. Direct antiviral therapy using antiviral therapy with high resistance barrier drugs

which reduce HBV DNA > 2 log reduction from the baseline within 2 weeks has shown

better survival from 17% to 57% in an RCT. (59) Dual antiviral therapies, although shown

to improve renal functions, did not improve the overall antiviral potency. A recent pilot

study published showed a good response to infection in HBeAg + patients with FMT.
(107)
HCV infection with detectable viral RNA can be effectively treated with new direct-

acting antiviral therapy. (1,59,60)

Alcoholic hepatitis

Patients with AH need nutrition and psychological support. Among the medical

management, tailored nutrition, psychosocial rehabilitation, and treatments aimed at

suppressing inflammation or TNF- production (such as corticosteroids or pentoxifylline)

steroids are the best available pharmacological option in severe AH and are the first-line
treatment for patients, it is recommended by AASLD, EASL, and ACG. So, AH patients

need assessment for treatment with a corticosteroid. The response is seen in up to 60% of

the patients, with better short-term mortality. (24)

Response can be assessed with Lille’s

model score on day 7, and if there is no improvement on day 7, they should be evaluated

for transplantation. Among the patients receiving steroids, almost one-fourth may develop

an infection during the therapy. (61)

If liver transplantation is not available in these patients, other therapies can be explored,
(62)
like granulocyte-colony stimulating factor (G-CSF) therapy. G-CSF was found to

mobilise the hematopoietic stem cells and induce liver regeneration. In patients with

alcoholic hepatitis, a 5-day G-CSF administration (10μg/kg/d, subcutaneously) mobilised

CD34+ stem cells, increased circulating hepatocyte growth factor, and induced

proliferation of hepatic progenitor cells in liver biopsy specimens, which improved

(63)
survival and reduced renal dysfunction. But in a recent study published, 176 patients

with ACLF (EASL-CLIF criteria) were randomly assigned to receive G-CSF (5μg/kg

daily for the first 5 days and every third day thereafter until day 26) plus standard medical

therapy (SMT) (n = 88) or SMT alone, which showed no survival benefit with a 90-day

transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio

[HR] 1.05; 95% CI 0.711–1.551; p = 0.805). (110) Antibody against IL-2 receptor antibody

also is a promising therapy, in a study, where in vitro usage of Basiliximab showed

improvement in steroid resistance. (62)

Pentoxifylline, anti- TNF- therapy, N- acetylcysteine, and s- Adenosyl methionine or

recently TLR 4 antagonist or IL-1 antagonist have been variously used. Recently, the

modulation of the gut microbiome has been assessed for treatment, as it seems very

important in altering the resident microbiome and thus plays an important emerging role.
(83)
If no options are available, one can use artificial liver support systems (ALSs),
although significant beneficial effects are not demonstrated, nevertheless, one can always

use it as bridging therapy if required, especially among those with renal impairment. (84)

Auto-immune hepatitis-

Patients with AIH can present with an ACLF, or acute failure-like presentation, in up to

20 percent of cases. Steroid therapy in these patients can be tried, but it is controversial.

Some studies favour the therapy as having a better outcome, but it's still controversial. (65)

For the therapy with other immunosuppression like tacrolimus or mycophenolate mofetil
(65)
the data is inconclusive, although some studies also support these drugs. Continuous

assessment of these patients is necessary; if there is no improvement in the MELD scores

within 7 days of treatment, they should be evaluated for LT.

DILI (drug-induced liver injury)

Drugs causing liver injury can act as the acute insult that can precipitate ACLF with

underlying NAFLD; the incidence can be up to 11.6%, and they have a very high

mortality rate of 57 percent. In India anti-tubercular treatment forms a very important

cause of DILI. (66) However, in most of the patients, no identifiable cause for acute insult

can be present, so in that case, these patients need monitoring, identification, treatment of

the complications, and transplant evaluation as indicated, along with organ support for the

organ failures. (66,67)

Treatment of complications

Hepatic encephalopathy

HE is seen in up to 40% of the cases associated with high mortality. Arterial ammonia

>140 mcg/dl with grade III-IV HE has a high mortality. Ammonia-lowering therapy using

lactulose therapy and Rifaximin therapy has shown significant improvement in HE scores.

Mechanical ventilation may be required for an advanced grade of HE. (67,68)

Acute kidney injury

AKI is diagnosed as discussed above has increased mortality by up to 38% at day 7. (69–71)

Adequate fluid resuscitation, avoiding and withdrawing the nephrotoxic agents, and

targeting the PIRO (predisposition, infection, inflammation, response, and organ failure)
(1)
by using anti-inflammatory strategies like albumin are important. Albumin (20 %

albumin IV infusion at a dose of 1g/kg followed by 20-40 g/day (60) and N-acetyl cysteine

infusion at 100 mg/kg/24 hours can be useful in the patients. (1,38) Volume expansion with

albumin, either alone or along with vasoconstrictors, may be used as an excellent

(72-75)
treatment option. Terlipressin, along with albumin infusion, is the standard of care

in patients with ACLF who develop HRS. Studies have shown that a reduction in the

serum creatinine has better 90-day survival, especially among those with grade III ACLF,
(75)
or can help as a bridge to survival after transplant. The dosage can vary, as

demonstrated by various trials. Various studies have used terlipressin at a dose varying

from 0.5–1 mg every 4–6 hours to as high as 2–12 mg of total dose per day and shown
(71)
clinical improvement. Another role of terlipressin is in patients with SBP, prevention

of PICD, variceal bleeding, and perioperative management, especially in the setting of LT.

Hepatorenal syndrome (HRS) reversal is defined as a decrease in serum creatinine to ≤1.5

mg/dL (≤133 µmol/L), which is reported in 35%–80% of patients with terlipressin

(60,65) (1,3,39)
therapy. It should be noted that non-responders have very high mortality.

ACLF patients requiring renal replacement therapy (RRT) have a severe grade of ACLF.

Mortality in critically ill patients with a need for RRT is substantially high, independent
(76)
of the LT options. Upon failure of the medical treatment, RRT should be offered.

Common indications where it should be considered are severe volume overload,

(77-79)
hyperkalaemia, hyponatremia, and severe metabolic acidosis. Especially the sicker

group of patients benefits from continuous venovenous hemodialysis (CVVHD) over

conventional hemodialysis or slow low-efficient dialysis (SLED). CVVHD is probably

safe because it reduces the fluctuations in the mean arterial pressure and cerebral
(68)
perfusion pressure (CPP). The postoperative mortality of liver transplant recipients

requiring RRT is increased compared with those not needing renal support (15% vs. 4%

at 3 months and 30% vs. 10% at 1 year, respectively), but similar to that observed in

patients requiring the initiation of RRT post-transplant (21% and 33%, respectively). (76,80)

Respiratory failure

Respiratory failure requires urgent care in the ICU. Initially, non-invasive ventilation

strategies are to be considered except in cases of uncooperative or encephalopathic

patients. Common indications like pneumonia, volume overload, ARDS (acute respiratory

distress syndrome), or advanced encephalopathy for airway protection are also important

and should be kept in mind. Intubation before transplantation increases the incidence of

postoperative pneumonia (15% vs. 5%, p = 0.02) as well as post-operative mortality (38

vs. 23%; p < 0.01). (1,81).

Circulation failure and vasopressors

Early goal-directed fluid therapy should be taken care of within the first 6 hours, similar

to the surviving sepsis campaign guidelines. The goal of such therapy is to maintain
(82,83)
MAP>65mm of hg. The common resuscitation fluids used are crystalloids and 5%
(84)
albumin and the preferred vasopressors commonly used are norepinephrine,
(72-
epinephrine, or terlipressin. IV fluids with balanced solutions improve renal function.
74)
Use of IV hydrocortisone in refractory shock at a dose of 200 mg IV (4 divided doses)
(72)
can also be beneficial, as these patients have been demonstrated to have a low adrenal

reserve. (85)
Definitive Liver transplant as option– sickest first

LT in ACLF needs to be prioritised if required. When the UNOS database analysed

patients with ACLF-III and those with the status-1a listing, it was demonstrated that

patients with ACLF-III showed significantly greater 14-day mortality (sub-distribution

hazard ratio of 1.45, 95% confidence interval: 1.31–1.61) compared with status-1a
(86)
candidates; these results were independent of MELD-Na score. At 30 days, mortality

was high in patients on the waiting list without LT with the increasing number of OFs,

and liver transplantation could be done in only about 25% of the patients. Recent studies

by Thuluvanath et al demonstrated that, with LT, the 90-day patient survival was 90%

and the one-year survival was 81% even in the presence of 5–6 OFs. (6,87) The futility of a

liver transplant should also be well assessed over time. A liver transplant is considered

less beneficial if 5-year survival is 50%. Patients should be considered for early transplant

with MELD score >28, AARC score >10, high-grade HE, and in the absence of > 2 organ

failure or overt sepsis as there is a high chance of failure of conservative management and

high mortality. (34,88,89)

Overall, some ACLF patients may show improvement with conservative treatment, but

even after recovery from the initial insult, there is an increased likelihood of

decompensation in the future and an inherent high mortality rate in the recovered patients
(90)
of up to 40%–50% at 6 months. But as shown in the Canonic study, transplanted

ACLF patients had a very good long-term survival rate of up to 80%. (91)

Relative contraindications for LT

The relative contraindications for LT for other causes also hold good for LT in ACLF

patients. Active alcoholism is a contraindication; most countries need at least 6 months of

abstinence, but this can be relative and has been challenged by a study by Mathurin et al.
(86)
Respiratory failure or active lung infection can have poor survival which can be

present at the time of presentation or during the care and can be considered a
(92)
contraindication. In patients with respiratory failure, the best time for LT is when
(87)
improvement is seen in PaO2/FiO2 >150. Systemic infections can be one of the

precipitating causes or initial events, as defined in the western definition, at the time of

presentation. So, this can be a general contraindication if active, especially with a culture-
(93)
positive infection or fungal sepsis. However, after control of infection, or in the case

of special infections like cholangitis in primary sclerosing cholangitis, it is not considered

(94)
a contraindication. Uncontrolled HIV infection is also a contraindication. A

psychiatric condition is also contraindicated as it may hamper the patient's self-care.

Transplantation in alcoholic hepatitis

Since the outcome in these patients is very poor, especially with severe AH or steroid

non-responders. LT becomes a useful salvage option for improving survival. But the

problem is, these patients would have actively taken alcohol even just before presentation.
(96)
Many transplant centres recommend a minimum of six months of abstinence from

alcohol so that recovery can be given a chance even before considering an evaluation, so
(97,98)
LT for severe AH has remained a controversial subject. Dom et al. showed that

longer periods of abstinence from alcohol beyond six months can have a stronger
(99)
prognostic value for a low risk of post-transplant relapse at 5% per month. But in a

landmark case-control prospective study, Mathurin et al. challenged the "six-month rule."

In this study, they selected 26 patients with severe AH who did not respond to steroid
(100-101)
therapy to receive LT (6-month survival: 77% vs. 23%, P<0.0001). Similarly, in

the UNOS dataset comparing alcoholic cirrhosis versus AH, the five-year graft survival

was 73% and 75% (P = 0.97), and the five-year patient survival was 78% and 80% (P =
0.90), respectively. (98) So currently, patients with severe alcoholic hepatitis who are non-

responders to the medical therapy, with the presence of a strong social support network,

insight into the disease process, the absence of co-existing psychiatric disorders,

agreement with adherence to lifelong abstinence, and complete agreement by the liver

transplant committee, Recently, the mean rate of adding patients with acute alcohol-

associated hepatitis to the liver transplant waiting list was 2.3% (0.7%), and their rate of

receiving liver transplants was 4.4% (1.9%). (92)

Artificial liver support system (ALSS) as bridging therapy

Bridging devices fall into one of two categories: liver support devices (biological and

nonbiological) and hepatocyte transplantation. Extracorporeal liver-support systems have

shown a good safety profile. However, they have not shown major improvements in

synthetic function. Plasma exchange improves the biological response. Multiple

randomised controlled trials in patients with ACLF have shown better improvement in

circulatory dysfunction, HE, hepatorenal syndrome, and immune dysfunction without

much significant improvement in transplant-free survival. (105)

Artificial liver support systems (ALSs) are safe and have demonstrated the following

benefits: improvement of biochemistry, hemodynamic status, and hepatic encephalopathy.

The thinking behind its usage is that the cellular damage in ACLF is extensively driven

by an increased "cytokine burst", with an accumulation of cytokines and vasoactive

(12,105)
substances in the blood. Artificial extracorporeal liver support (ECLS) systems

remove water-soluble and albumin-bound toxins to maintain normal serum chemistry,

prevent further hepatic and organ system damage, and create an environment for potential

hepatic regeneration and recovery.

Hepatocyte transplantation with liver progenitor cells is another emerging bridging

therapy under study. However, current studies lack data on long-term safety and

effectiveness. Various cell-based therapies, augmentation of hepatic regeneration, and gut

modulation by faecal microbiota transplantation are interesting but still far from being

recommended as an alternative to LT. (12)

Way forward

• ACLF is a serious complication with high mortality.

• There is a need for a universally acceptable definition.

• Early diagnosis and management are the keys to survival.

• Early intervention at the stage of organ dysfunction can improve patient outcomes.

• The need to search for better biomarkers to detect organ failure early is an

important unmet need.

• Management currently largely relies on early identification and the provision of a

liver transplant. However, quite often, this is not feasible.

• There is a need for the development of effective non-transplant medical therapies

such as liver regeneration and cell-based therapies.

• Bridge therapies like plasma exchange, bio-artificial liver support systems, and

hemoperfusion systems are promising.

Fig 1: Various definitions of liver failure.
Illustrating the differences in the definition by various societies and its basis and time frame,
APASL- Asian Pacific Association for the Study for the Liver, EASL- European Association for
the Study of the Liver, NASCELD-ACLF- North American Consortium for the Study of End-Stage
Liver Disease's definition of acute-on-chronic liver failure. GI( gastro-intestinal bleed), hepatic
encephalopathy (HE), HRS(Hepatorenal syndrome), AKI (Acute kidney injury).
 Hepatic (Alcohol, virus, drugs, etc.)
and Non- hepatic triggers with primary
hepatic injury

Acute insult

Dysbiosis with increased

gut permeability
DAMPS – HMGB1, ATP, IL-
LPS / PAMPS and virulence 1,IL-33, S100 protein
factors PRR/TLR and various superfamily,
receptors mitochondrial DNA, N-
formyl peptides.

Innate immune system-

abnormal phagocytosis
and cell damage

Monocyte dysfunction Mitochondrial dysfunction Activation of Neutrophil

MERCTK positive cells do not mount response to (Decrease fatty acid bioactivation)
antigen and Kupffer’s cells

ER stress
Activation of NLRP3
inflammasome
Persistence of SIRS HMGB1 activation

TLR4–CD14–Lymphoctye antigen 96 (Ly-96 also known as MD2) receptor complex

assembly followed by recruitment of the adaptor molecules, myeloid-differentiation
factor 88 (MYD88) and TIR domain-containing adaptor molecule 1 (TRIF)

Downstream signalling cascades

Continued inflammatory response

 IMPROVEMENT
Secondary infection AND REVERSAL
OF CAUSE

Progression of organ
failures Reversal of the failure

Immunoparalysis
Fig 2: Insights into of Pathophysiology of ACLF.

Figure illustrates the importance of Gut-liver axis and immune activation, causing

SIRS which leads to various organ failures, LPS- lipopolysaccharides, DAMP- damage
associated molecular pattern’s, PAMP’S – pathogen associated molecular patterns, PRR/TLR-
pattern recognition receptors/TOLL like receptors, i-NOS- Nitric oxide synthase, ER-
endoplasmic reticulum, NLRP3-NLR family pyrin domain containing 3, RAAS-Renin-angiotensin-
aldosterone system, HMGB1-High mobility group box 1 protein. Above figure shows the systemic
inflammation triggered by the necrosis and release of DAMPS and PAMPS released with
bacterial translocation activate the immune system. This continued inflammatory response
causes the deleterious effects downstream. This causes the progression of organ failures,
subsequently this immune overdrive causes immune paralysis. Later persistent organ failures
results in high mortality.

Fig 3: Concept of Golden window.

This period may be considered as the initial 1-week period of the disease presentation. An acute
hepatic insult leading to hepatic decompensation is the main driver resulting in the subsequent
extra-hepatic organ failure. This is essentially due to the failure of recovery or regeneration. The
period from acute insult and the development of immune paralysis and subsequent the
development of sepsis is considered as the golden window of opportunity. Prevention of SIRS or
its progression to sepsis and using immune modulation in the golden window period provides
therapeutic opportunity and may benefit the patient. (1,32)

Fig 4: showing the histological patterns of ACLF showing the appearance of two patterns
(34)
described.
 ACLF

MELD <30 MELD >30

AARC<10 AARC>10

Acute insult
Conservative management No
improvement-
0/1 OF >2 OF
Conservative

No
improvement
AH- steroid, GM-CSF, FMT
AIH – Steroid etc.
Viral- antiviral (HBV) Organ support
Wilsons – PE LT /bridge therapy

Improved
Conservative
mangemnt

Sepsis → needs antibiotic

coverage → source control and
negative cultures for pursuing LT

Fig 5: Algorithmic approach for treatment.

AH- alcoholic hepatitis, AIH – auto-immune hepatitis, FMT- fecal microbiota transplant, LT-
liver transplantation, GM-CSF- granulocyte and monocyte colony stimulating factor, MELD -
Model for End-Stage Liver Disease, AARC-APASL ACLF Research Consortium, OF- organ
failures. CST- continue same treatment., PE- plasma exchange.

APASL (1) NASCELD (6) EASL (4)

Defined Patient First episode in Patients with acutely Acute decompensation in

group compensated cirrhosis decompensated cirrhosis patient with or without
or non-cirrhotic CLD cirrhosis, with or prior decompensation.
without prior episode(s)
of decompensation.

Acute insult Hepatic only Extra-hepatic Hepatic or extra-hepatic

Variceal bleed is
Variceal bleed is
considered as insult if
considered as precipitant
it results in liver failure

Organ failure Liver - central to Any of the 4 Any of 6

pathogenesis
Cardiac (shock), hepatic Liver/cardiac/renal
encephalopathy, renal
/circulatory/coagulant/respiratory
(need for dialysis),
respiratory (need for
mechanical ventilation)

Duration Acute insult leading to No specific duration No specific duration specified

development of ACLF specified
is 4 weeks

Definition basis Liver involvement is Existence of 2 or more Based on existence of 1 of the

the central cause and organ system failures. six organ failures and CLIF -C
subsequently other score is used to categorize.
extrahepatic organ
failures follow

AARC score is used to

stratify

Mortality Grade 1- 13% 2 OF-49% Grade1-20%

 Grade 2-45% 3 OF-64% Grade2-30%

Grade 3- 86% 4 OF-77% Grade3-80%

Table 1: Definitions by various societies and its differences. ACLF (Acute on chronic liver
failure), APASL (Asian pacific Association for study of liver), NASCELD (North American
Consortium for the Study of End-Stage Liver Disease), EASL (European association of study of
liver), APASL ACLF research consortium (AARC) score, Model for end stage liver disease
(MELD) and other CLIF Consortium acute-on-chronic liver failure (CLIF C- ACLF), CLD
(Chronic liver disease), OF (Organ failure).

European Association
for the Study of Liver- North American Consortium
Asian Pacific
ORGAN Chronic Liver failure for Study of End-stage Liver
Association for the
FAILURE organ failures definition Disease organ failures
Study of the Liver
Based on CLIF-C ACLF definition
score
Total bilirubin ≥5
Liver mg/dL Bilirubin >12 mg/dL –
INR ≥1.5
Coagulation INR ≥1.5 INR ≥2.5 –

AKIN criteria
Creatinine: increase > Creatinine level of ≥2.0
Need for dialysis or other forms
Kidney 0.3 or 1.5-fold over 48 mg/dL or renal
of renal replacement therapy
h to: >/= 0.7 & 1.5 replacement

HE (West-Haven) HE (West-Haven) grade

Brain HE (West-Haven) grade 3–4
grade 3–4 3–4
Shock with MAP<60 mm of hg
Vasopressor usage
or drop of > 40 mm of hg from
Circulation – (terlipressin and/or
the baseline despite adequate
catecholamines)
fluid resuscitation
PaO2/FiO2 of ≤200 or
Respiration SpO2/FiO2of ≤214 or Need for mechanical ventilation
mechanical ventilation
Table 2: Organ failures definitions ,
Organ dysfunction defined as [coagulation – INR>1.5, Renal- creatinine (1.1-1.5 mg/dl), cerebral
(HE grade I-II), circulatory- <Systolic BP <70 mm of hg, respiratory PaO2/FiO2 200-300].
CLIF C ACLF score 10 x [0.033 x Clif OFs + 0.04 x Age + 0.63 x Ln(WBC) – 2]

AARC scoring

Points Total HE grades INR Lactate Serum

bilirubin (mmol/l) Creatinine
(mg/dl) (mg/dl)

1 <15 0 <1.8 <1.5 <0.7

2 15-25 I-II 1.8-2.5 1.5 -2.5 0.7-1.5

3 >25 III-IV >2.5 >2.5 >1.5

AARC score in ACLF grade 1= 5-7, grade 2 = 8-10, grade 3 = 11-15.

Table 3: Prognostic scoring systems - CLIF – SOFA core & AARC scoring. (1,2,109)
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